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Aging and disease    2020, Vol. 11 Issue (3) : 692-704     DOI: 10.14336/AD.2019.0814
Review |
Implications of Long Non-Coding RNAs in Age-Altered Proteostasis
Cristina-Sorina Catana1, Catalina-Angela Crișan2, Dana Opre3, Ioana Berindan-Neagoe4,5,6,*
1Department of Medical Biochemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
2Department of Neurosciences, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
3Department of Psychology, Babeș-Bolyai University, Cluj-Napoca, Romania
4MEDFUTURE - Research Center for Advanced Medicine, Cluj-Napoca, Romania
5Research Center for Functional Genomics, Biomedicine and Translational Medicine, Institute of Doctoral Studies, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
6Department of Experimental Pathology, “Prof. Dr. Ion Chiricuta” Oncology Institute, Cluj-Napoca, Romania
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This review aims to summarize the current knowledge on how lncRNAs are influencing aging and cancer metabolism. Recent research has shown that senescent cells re-enter cell-cycle depending on intrinsic or extrinsic factors, thus restoring tissue homeostasis in response to age-related diseases (ARDs). Furthermore, maintaining proteostasis or cellular protein homeostasis requires a correct quality control (QC) of protein synthesis, folding, conformational stability, and degradation. Long non-coding RNAs (lncRNAs), transcripts longer than 200 nucleotides, regulate gene expression through RNA-binding protein (RBP) interaction. Their association is linked to aging, an event of proteostasis collapse. The current review examines approaches that lead to recognition of senescence-associated lncRNAs, current methodologies, potential challenges that arise from studying these molecules, and their crucial implications in clinical practice.

Keywords lnc RNA      cancer metabolism      age-related diseases      proteostasis      HOTAIR     
Corresponding Authors: Berindan-Neagoe Ioana   
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These authors contributed equally to this work.

Just Accepted Date: 02 October 2019   Issue Date: 13 May 2020
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Catana Cristina-Sorina
Crișan Catalina-Angela
Opre Dana
Berindan-Neagoe Ioana
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Catana Cristina-Sorina,Crișan Catalina-Angela,Opre Dana, et al. Implications of Long Non-Coding RNAs in Age-Altered Proteostasis[J]. Aging and disease, 2020, 11(3): 692-704.
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lncRNAARDsFunction in proteostasisTarget geneThe cellular and molecular
effects of the lncRNA
LncRNA-MALAT1-highly expressed in cancer; Diabetic nephropathy;
-atherosclerosis; - neurodegenerative processes

Protein turnover Scaffolding Autophagy
-HMGB1; β-catenin;
- B-MYB; - PDGF-BB - ATG7 (miR142-3p)
-Inhibition of Tumor Cell Apoptosis;
- kidney fibrosis; restored podocytes function; - Phenotypic switching of VSMCs

[34], [77], [81], [82]
LincRNA-p21-skin cancer
-colorectal cancer -prostate cancer

Protein turnover
HIF-1α β-catenin Jun B mRNA
cell cycle arrest; apoptosis in keratinocytes; represses translation of cancer proteins[7], [37], [54], [83], [84]
LncRNA CND1/cyclin D1- many cancer types;
- BCL2; -breast cancer
-Protein turnover- TLS
-cyclin D1
- cell cycle regulator in cancer
-benefits in breast cancer therapy
[38], [39]
LncRNA-HOTAIR-breast, gastric, and colorectal tumors;
- nasopharyngeal cancer
-Protein turnover;
- Scaffold function
- Snurportin-1; Ataxin-1
•cell proliferation, invasion, aggression, and metastasis; inhibition of apoptosis
• prevents cellular senescence
[31], [29], [42], [45]
Lnc AS Uchl1-neurodegenerative diseases;
-cancer; -auditory cortex senescence
Protein turnover-MDM2;
-UPS-related proteins: p53, p14; ARF, p27KIPI, ubiquitinated proteins, monoubiquitin, BE1, PSMA7
- intensifies translation of UCHL1, which plays an important role in the UPS system[49], [50], [51]
-gastric carcinoma -prostate cancer
-Protein turnover;
-Membrane trafficking
E2F1; P27Kip1
-Inhibits cellular proliferation
- a growth arrest lncRNA
[52], [85]
Lnc RNA PANDA-senescence.Membrane traffickingFAS; BIK; p53inhibits DNA-damage-induced apoptosis[86]
Lnc ANRASSF1-breast, osteosarcoma, colorectal, liver, bladder, renal cell carcinoma-Membrane trafficking;
-Scaffold function
PRC2Control of proliferation, metabolism, apoptosis and senescence; histone modifications[36], [87]
- is expressed in response to oxidative stressMembrane traffickingTDP-43, modulates Cdk6 levelscontrolling cell-cycle progression[88]
-widely upregulated in cancer tissues-Autophagy
-Protein trafficking
cellular senescence[70], [36]

-ovarian cancer;
- tongue squamous cell carcinoma
AutophagymiR-675-A key synthesis-related factor of miRNA related to tumor cell activities;
- cellular proliferative and invasive capacities
LncRNA HULC- tumor chemoresistance;
-hepatocellular carcinoma
USP22/COX-2" axis; - Sirt1
Increase triglyceride and cholesterol levels in hepatoma cell[64]
Lnc MEG3-colorectal cancer
- Huntington’s disease
Growth arrest
-blocks apoptosis[20]
LincRNA H19-breast cancer;
-human tumor growth; - Gastric Carcinogenesis
Scaffold function-E2F1, PRC2, HuR, KSRP-suppression of RBmRNA via miR675;
-DNA methylation; cell division cycle
[102], [103], [104]
LncRNA PRNCR1-prostate cancer
Scaffold function- AR- regulation of AR-dependent gene activation events-[74], [90]
LncRNA PCGEM1-prostate cancerScaffold function- AR-tumor type-specific super-enhancer[74], [90]
LncTERC-premature neural aging in terc KO miceScaffold functionTRF1, TRF2- Promotion of telomere extension
-controlling the survival of NSCs - prevention of premature senescence and aging
[2], [30], [91]
Lnc TERRA-neural agingScaffold functionTRF1, TRF2-Suppression of telomere extension
-survival of NSCs
[2], [30]
Lnc ANRIL-upregulated in prostate cancer;
- myocardial infarction - hyper-cholesterolemia
-Protein turnover;
-Scaffold function
- let-7a/TGF-β1/Smad signaling pathway
-proliferation and migration of prostate cancer cells
- antisenescence function -histone modification
Table 1  lncRNAs in proteostasis.
Figure 1.  Altered HOTAIR regulation contributes to ARDs/ senescence. HOTAIR, overexpressed during aging, activates proliferation and invasion. miR-141 levels are inversely correlated with malignacy by binding to this lncRNA and thus abrogating its transcription. Both interact with/are linked to Argonaute 2 (Ago 2) complex. A positive feedback mechanism from senescent cells upregulates miR-141. The level of HOTAIR could be reduced in a micro-dependent manner by an RNA binding protein (RBP), the senescence-repressor HuR, which degrades this lncRNA. In addition, HOTAIR facilitates ubiquitination and proteolysis of Snurportin-1 and Ataxin-1. HOTAIR interacts with E3 ubiquitin ligases and with their ubiquitination substrates, Ataxin-1 and Snurportin-1. HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b and accelerates their degradation. HOTAIR has a key role in cellular senescence through inducing extended expression of NF-κB target genes and also NF-κB activation during DNA damage. An NF-κB-HOTAIR axis leads to a positive-feedback loop cascade contributing to cellular senescence and chemotherapy resistance in cancers. Overexpression of miR-203 inhibits HOTAIR, triggering epithelial- mesenchymal-transition (EMT), therefore inducing cell-cycle arrest and apoptosis. The expression of phosphatase and tensin homolog (PTEN), E-cadherin and claudin is increased by blocking invasion and metastasis while p21 and p27 are downregulated.
Figure 2.  Mechanism by which lncRNA HULC activates tumorigenesis. Abbreviations: CLOCK- circadian locomotor output cycles kaput; E2F1-transcription factor involved in cell cycle regulation and apoptosis; HCC- hepatocellular carcinoma; HIF-1α- hypoxia-inducible factor 1-alpha; HMGA2- high mobility group A protein 2; HULC- highly up-regulated in liver cancer; PRKACB- protein kinase cAMP-activated catalytic subunit beta; PTTG1- pituitary tumor transforming gene; siRNA- small interfering ribonucleic acid; TWIST- the basic helix-loop-helix transcription factor ; YAP- yes-associated protein 1. lncRNA HULC, highly expressed in liver cancer, modulates the oncogene HMGA2 to activate tumorigenesis and interacts with the CLOCKmRNA, leading to the enhancement of its transcription. HMGA2 plays an essential role in the genesis of lung cancer, gastric cancer and colorectal carcinoma. HULC could be considered a molecular sponge which sequester certain miRNAs such as miR-186, miR-107 as well as miR-372, therefore reducing the translational repression of HMGA2, E2F1 and PRKACB. The expression level of HULC is positively correlated with HMGA2 and opposite to miR-186. In human HCC tissues, HULC upregulated HMGA2 expression via sequestering miR-186 promotes tumorigenesis. Moreover, HULC induces the expression of cyclin A and IL-15 in a dose-dependent manner. In HCC, HMGA2 is inhibited by miR-107 and let-7 miR-107 in breast cancer as well as siRNA as a consequence of HULC inhibition.
lncRNA/expressionImplication in neurodegenerative disordersAbnormalities in neuronal process/ Clinical featuresReference
-expressed in the nucleus and cytoplasm
-upregulated in the hippocampus of old mice;
-downregulated in old induced striatal medium-sized spiny neurons (MSSNs); - PTEN/PI3K/AKT signaling cascade
-cognitive decline
-downregulated in HD brain tissue - synaptic plasticity in neurons
[30], [92]
SORL1-AS- upregulated in AD disease brain affecting Aβ formation-AD;
-Protein aggregation; -cognitive impairment
[30], [93]
-spatiotemporal expression
- Regulation of Six3 targets through interactions with Eya proteins and the chromatin-modifying protein Ezh2;- adult mouse neurogenesis[94]
17A-upregulated in frontal and temporal cortices
-increases Aβ secretion
-Abolish GABA B2 intracellular signaling
MALAT-1- upregulated in human aged SVZ;
-upregulated in the hippocampus of old mice; - scaffold for proteins and RNAs
-cognitive decline;
-neurodegeneration; -PD
[30], [96], [97]
UCHL1-AS-downregulated in murine dopaminergic cells;
- regulated by a transcription factor Nurr1 required for dopamine cells differentiation
- Neurodegeneration;
ANRIL-altered expression in all tissues-AD;
- Neurodegeneration;
HOTAIR- high expression of HOTAIR promotes PD-PD[99]
BACE1-AS- Increases BACE1 mRNA stability and Aβ42 formation- up-regulated in AD brains[100], [101]
Table 2  Senescence- associated lncRNAs and neurodegenerative disorders.
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